Polysaccharide capsules and methods of preparation

ABSTRACT

The present invention is directed to seamless capsules and methods for making seamless capsules having a high oil content. More specifically, the present invention is directed to seamless capsules, and methods for making seamless capsules, made from a process involving the steps of: (a) preparing an emulsion comprising oil, water, an emulsifier, and at least one of a water-soluble monovalent metal salt, polyvalent metal salt, and an acid, wherein said oil is present in an amount of at least 50% by weight of said emulsion; with the proviso that said emulsion does not contain marmelo mucilage; and (b) adding portions of said emulsion to an aqueous gelling bath comprised of at least one ionic polysaccharide, thereby encapsulating said portions of said emulsion in a polysaccharide gel membrane, and optionally (c) drying the resulting capsules by removing water. The capsule is, for example, an alignate gel. The capsules of the invention are suitable for a variety of applications, e.g. pharmaceutical, nutraceutical, veterinary, agricultural, cosmetic, or food applications.

The present invention pertains to oil-containing seamless capsuleshaving a polysaccharide gel membrane on the outer surface thereof, andmethods for preparation of such capsules. The inventive capsules aresuitable for pharmaceutical, nutraceutical, veterinary, food,agricultural and specialty applications such as paintballs.

BACKGROUND OF THE INVENTION

It is well known that gelatin has been used, inter alia, in a wide rangeof food products, such as gelatin containing courses, compressed meats,pastries, and the like. It is also well known that gelatin has been usedto deliver pharmaceuticals in capsule form for more than one hundredyears. It has many useful physical and chemical properties, whichsupport this broad range of utility.

The primary sources of gelatin are from bovine animals and pigs. Thesource of gelatin can be a problem for potential areas of use or forparticular consumers. Large groups of people around the world cannotingest any products derived from these animals, because of religiousbeliefs or because of dietary requirements and preferences.Additionally, as there has recently been at least one alleged instanceof cross-species contamination from cattle to humans (at least onealleged instance with bovine spongiform encephalopathy, BSE, or “Mad CowDisease” in the United Kingdom), the use of uncontrolled by-productsfrom animals has lost some level of commercial acceptance. It has becomeapparent that replacement compositions for gelatin, which are notderived from animals, are desirable.

For example, U.S. Pat. No. 5,942,266 ('266 patent) sets forth one methodfor capsule formation using alginates which comprises contacting liquiddrops of a composition of an aqueous solution of a water-solublemacromolecular substance (such as guar gum) at least a portion of whichis marmelo mucilage, an oleaginous substance (such as animal orvegetable oil), a water-soluble polyvalent metal salt (such as calciumchloride), with an aqueous solution of a water-soluble salt of analginic acid, thereby forming a water-insoluble film of alginic acidsalt on the outer surface of the liquid drop. As reported in the '266patent, the amount of oleaginous substance that is encapsulated can bein the range of 10% to 95% by weight of the liquid drop. In order toencapsulate such a relatively large amount of oleaginous substance(preferably 30-85% by weight of the liquid drop), the composition of theliquid drop in the '266 patent is very complex; requiring the presenceof exacting amounts of macromolecular substance, oleaginous material,polyvalent metal and other salts; and the essential requirement ofmarmelo mucilage. The oil-entrapment with the use of marmelo mucilageled to formulations where separation began after only 30 minutes, confercolumn 6, lines 27-30.

JP patent application no. 59166916 describes enteric soft capsulesobtained by dual nozzles techniques. These techniques are limited to theprovision of spherical capsules. Another frequent problem with capsulesprepared by these techniques is capsules with walls of uneven thickness,due to density differences of the different phases during preparation.

JP 6055060 and JP 6079165 concern seamless coating film capsulescontaining surfactant and detergent preparation obtained by the use ofmultiple nozzles technique.

Thus, it can be seen that an improved, simpler method is needed forpreparing stable robust seamless capsules comprising relatively largeamounts of active materials.

Other references such as U.S. Pat. No. 4,702,921 disclose thepreparation of capsules containing alginate gel membranes, but appear touse an amount of water that makes the capsules difficult to dry.

The present inventors have overcome the problems associated with theprior art wherein the capsules contain too much water.

It has now been found in accordance with the present invention thatemulsions comprised of relatively large amounts of an active material,such as an oil, or added other component, can be prepared that offer analternative to complex combinations of active material, water, and aplurality of other components. Accordingly, the objects of the presentinvention include: 1) a method of preparing seamless capsules of highstability, using water emulsions containing relatively large amounts ofoils, 2) a simple method of preparing seamless capsules of highstability that encapsulate the aforementioned water emulsions of oilswith other solid, or liquid or gaseous components added, in apolysaccharide gel membrane, and 3) optionally, a method of drying andcoating the polysaccharide capsules of emulsion for a subsequent use.Furthermore the shape of the capsules of the present invention can bedetermined prior to the preparation, and the capsules of spherical,oval, oblong or cylindrical shape prepared according to the methods ofthe present invention have an uniform wall thickness. The capsules ofthe present invention have an excellent integrity and storage stabilityover a prolonged period of time.

SUMMARY OF THE INVENTION

Specifically, this invention is directed to a method for preparingseamless capsules having a polysaccharide gel membrane on the outersurface comprising the steps of (a) preparing an emulsion of oil, water,an emulsifier, and at least one of a water-soluble monovalent metalsalt, polyvalent metal salt, and an acid, wherein the oil is present inan amount of at least 50% by weight of the emulsion; with the provisothat the emulsion does not contain marmelo mucilage, and (b) addingportions of the emulsion to an aqueous gelling bath comprised of atleast one ionic polysaccharide, thereby encapsulating the portions ofemulsion in a polysaccharide gel membrane, and optionally (c) drying theresulting capsules by removing water.

The present invention is also directed to seamless capsules obtained bythis method.

In a preferred embodiment of the invention, the method of preparingseamless capsules further comprises the step of adding a further solid,or liquid or gaseous component prior to step b) to at least one of saidoil, water, emulsifier and at least one of water-soluble monovalentmetal salt, polyvalent metal salt, and acid prior to or after formationof the emulsion and mixing to a dispersion.

The present invention also comprises seamless capsules thereby obtained.The capsules of the invention can be made in a variety of shapes.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that relatively simple wateremulsions containing relatively large amounts of oils can beencapsulated in polysaccharide gel capsules. A method of preparing theseamless capsules having a polysaccharide gel membrane on the outersurface comprises the steps of (a) preparing an emulsion comprising oil,water, an emulsifier, and at least one of a water-soluble monovalentmetal salt, polyvalent metal salt, and an acid, wherein the oil ispresent in an amount of at least 50% by weight of the emulsion; with theproviso that the emulsion does not contain marmelo mucilage, and (b)adding portions of the emulsion to an aqueous gelling bath comprised ofat least one ionic polysaccharide thereby encapsulating the portions ofthe emulsion in a polysaccharide gel membrane, and optionally (c) dryingthe resulting capsules.

The present invention requires the oil to be present in an amount of atleast 50% by total weight of the emulsion. This means that the oilcontent is calculated based on the total weight of the oil, water,emulsifier and water-soluble monovalent metal salt, polyvalent metalsalt and acid. The emulsion of the present invention can be used as acarrier or vehicle for a variety of ingredients as discussed below. Itshould however be clear that the at least 50% oil content does not takeinto account the amount of any other components added prior to or afterformation of the emulsion.

The oil and water emulsion that can be encapsulated within the scope ofthe present invention is an emulsion wherein the oil is selected fromany oil, or combination of oils, that find utility in an encapsulatedform, for example, for use in the pharmaceutical (pharmaceutical hereinincludes veterinary and nutraceutical), food, nutritional, cosmetic,agricultural, and the like industries. Suitable oils include, withoutlimitation, oils derived from animals, plants, microorganisms, orextracts thereof; oils that are chemical compounds derived by syntheticor other means, or formulations thereof; oils that are fatty acids,esters, or derivatives thereof; or oils that may be a pharmaceuticallyactive agent, a nutritional supplement, flavor oil, or a food. Oilswithin the scope of the present invention also include oils that act ascarriers or solvents for oil-soluble active materials such as anoil-soluble pharmaceutically active agent, a nutritional, flavor,fragrance, supplement, or a food. Other oils within the scope of thepresent invention are those that include naturally occurringemulsifiers. One such oil is soy oil, which contains lecithin. Lecithinis useful in food manufacturing as an emulsifier in products high infats and oils. Preferred oils within the scope of the present inventionare those that are a liquid, or that can be made into a liquid at atemperature in the range of, for example, 20° C. to 95° C.

An emulsion of oil and water is defined as a heterogeneous system,wherein the oil and water are immiscible and either 1) the water isintimately dispersed in the oil, or 2) the oil is intimately dispersedin the water, in which the dispersed material is in the form ofdroplets. If left alone, the dispersed droplets will coalesce to formlarger and larger droplets, until all of the dispersed phase hascoalesced. Emulsifying agents, or emulsifiers, are used to preserve theintegrity of the dispersed droplets and prevent the separation of thetwo phases. To enable emulsifiers to prevent the separation of the oilphase and the water phase, the emulsifiers preferably have distinctchemical characteristics. Among the preferred characteristics of anemulsifier are that they possess 1) hydrophilic (water-soluble) and 2)lipophilic (oil-soluble) groupings in their molecular structures. Theeffectiveness of an emulsifier depends upon the balance of theweight-average molecular weight of the hydrophilic and lipophilicgroups. The balance, i.e., the hydrophilic-lipophilic balance(hereinafter termed “HLB”) has a value that can range from 1 upwards. Ingeneral, emulsifiers with lower HLB values, for example 3-9, are moresuitable for preparing water-in-oil emulsions, whereas emulsifiers withhigher HLB values, for example 9-18, are more suitable for preparingoil-in-water emulsions; however, there are emulsifiers that are usefulfor both types of emulsions.

Emulsifiers suitable in the context of the present invention arechemical compounds having both a hydrophilic group and lipophilic groupwherein the HLB value is in the range of 1 to 19. Examples of suchemulsifiers having HLB values in the range of 1 to 19 include, withoutlimitation, glycerin fatty acid esters, lactic acid esters ofmonoglycerides, lecithins, polyglycerol polyricinoleate, sorbitan estersof fatty acids, succinic acid esters of monoglycerides, calcium stearoyldilactate, citric acid esters of monoglycerides, diacetyl tartaric acidesters of monoglycerides, polyoxyethylene sorbitan esters of fattyacids, sucrose esters of fatty acids, and other emulsifiers. Emulsifyingagents may also include some particulate materials, such as, forexample, soot (water-in-oil emulsion stabilizer) or silica powder(oil-in-water emulsion stabilizer) as generally known. Preferredemulsifiers of the present invention are selected from the group ofpolyoxyethylene(20) sorbitan monolaurate (Sold under the name TWEEN 20)polyglycerol polyricinoleate (Sold under the name and trademark of PGPR90, by Danisco, Copenhagen, Denmark), calcium stearoyl-2-lactylate (Soldunder the name and trademark of VERV K, by American Ingredients Company,Kansas City. MO, USA), sorbitan monooleate (Sold under the name andtrademark of SPAN 80, by Aldrich Chemical, Milwaukee, Wis., USA), andmixtures thereof. More preferred emulsifiers are polyoxyethylene(20)sorbitan monolaurate, polyglycerol polyricinoleate, or mixtures thereof.

The emulsions of oil and water of the present invention contain at leastone of a water-soluble monovalent metal salt, a polyvalent metal salt,or an acid. For example, polysaccarides, such as alginates gel at lowpH, so acids, e.g., dissociated hydrogen ions, can be used in thepresent invention as gelling agents. A water-soluble monovalent metalsalt, polyvalent metal salt, or acid suitable for use in the presentinvention includes any inorganic or organic salt or acid that is capableof disassociating into a free ionic state in water, where the ions arecapable of forming a gel with an ionic polysaccharide. Suitable saltsinclude, without limitation, the salts of sodium, potassium, calcium,strontium, barium, aluminum, magnesium, other salts, and mixturesthereof. A preferred salt is calcium chloride, in either hydrated oranhydrous form. Increasing the salt content in the oil and wateremulsion, inter alia, increases the thickness of the polysaccharide gelmembrane when the capsules are formed, thereby making the capsulesstronger. The salt in the oil and water emulsion is present in at leasta gel-forming amount sufficient to adequately form polysaccharide gelmembranes surrounding portions of the oil and water emulsion.Preferably, within the scope of the present invention, the salt ispresent in the oil and water emulsion in an amount of up to 25% byweight of the emulsion, more preferably from 2% by weight to 15% byweight of the emulsion.

In a first embodiment of the present invention, the emulsion is anoil-in-water emulsion. The emulsion can be prepared by dissolving amonovalent or polyvalent metal salt (as discussed above), for example,calcium chloride dihydrate and at least one emulsifier (as discussedabove) for example, polyoxyethylene(20) sorbitan monolaurate, in water.The resultant solution may then be homogenized during which time an oil,for example, fish oil, soy oil, oleic acid, or mineral oil, can beslowly added to form a highly viscous oil-in-water emulsion. Apreferable amount of oil present in the oil-in-water emulsion is in anamount of 70% by weight to 98% by weight of the oil, water, emulsifierand water-soluble monovalent metal salt, polyvalent metal salt and acid,more preferably, in an amount of 85% by weight to 95% by weight of theoil, water, emulsifier and water-soluble monovalent metal salt,polyvalent metal salt and acid.

In a second embodiment of the present invention, the emulsion is awater-in-oil emulsion. The emulsion can be prepared by adding a watersolution of a monovalent or polyvalent metal salt (as discussed above)and at least one emulsifier (as discussed above), for example,polyglycerol polyricinoleate, to an oil (as discussed above) duringwhich time the mixture can be homogenized to provide the water-in-oilemulsion. A preferable amount of oil present in the water-in-oilemulsion is in an amount of 65% by weight to 85% by weight of the oil,water, emulsifier and water-soluble monovalent metal salt, polyvalentmetal salt and acid, more preferably, in an amount of 70% by weight to80% by weight of the oil, water, emulsifier and water-soluble monovalentmetal salt, polyvalent metal salt and acid. As set forth above, soy oilcontains the naturally occurring emulsifier lecithin. Water-in-oilemulsions of soy oil may be stable for a period of time long enough sothat the emulsion can be encapsulated without inclusion of additionalemulsifier.

In a third embodiment of the present invention, the emulsion is awater-in-oil-in-water emulsion. A water-in-oil-in-water emulsionprovides a means for encapsulating not only an oil, or an oil-solublesubstance, but also, a water-soluble substance, or a water-solubleactive ingredient. Accordingly, an inner phase comprised of a solutionof a water-soluble substance in water can be added to a middle phasecomprised of an oil (as discussed above) and an emulsifier (as discussedabove), for example, polyglycerol polyricinoleate, during which time themixture can be homogenized to form a water-in-oil emulsion. Theso-formed water-in-oil emulsion may then be added to an outer phasecomprised of a water solution of a monovalent or polyvalent metal salt(as discussed above) and an emulsifier (as discussed above), forexample, polyoxyethylene(20) sorbitan mono laurate, during which timethe mixture can be homogenized to form a highly viscouswater-in-oil-in-water emulsion. A preferable amount of oil present inthe water-in-oil-in-water emulsion is in an amount of 60% by weight to90% by weight of the oil, water, emulsifier and water-soluble monovalentmetal salt, polyvalent metal salt and acid, more preferably, in anamount of 70% by weight to 80% by weight of the oil, water, emulsifierand water-soluble monovalent metal salt, polyvalent metal salt and acid.

A preferred emulsion in the context of the present invention is anoil-in-water emulsion as discussed above in the first embodiment. Adrying process at an elevated temperature, for example, at about 60° C.,to remove water from the oil-in-water emulsion prior to itsencapsulation can eliminate a large portion of water from theencapsulation step, thereby providing a capsule in a relatively dryform, if a capsule in dry form is desired. The length of a separatecapsule-drying step can therefore be shortened. Additionally, as an aidto shortening the length of a capsule-drying step if one is desired,some of the water in the emulsion can be replaced with a water-misciblesolvent, for example an alcohol of C₁-C₄ straight or branched carbonlength, for example, ethanol.

In a preferred embodiment, the invention is directed to a method ofpreparing seamless capsules having a polysaccharide gel membrane on theouter surface, comprising the steps of preparing an emulsion comprisingoil, water, an emulsifier, and at least one of a water-solublemonovalent metal salt, polyvalent metal salt, and an acid, wherein saidoil is present in an amount of at least 50% by weight of said emulsion;with the proviso that said emulsion does not contain marmelo mucilage;and further comprising the step of adding a further solid, liquid orgaseous component prior to step b) to the at least one of oil, water,emulsifier, and at least one of a water-soluble monovalent metal salt,polyvalent metal salt, and acid prior to or after formation of the saidemulsion and mixing to a dispersion; and adding portions of the saiddispersion to an aqueous gelling bath comprised of at least one ionicpolysaccharide thereby encapsulating said portions of said dispersion ina polysaccharide gel membrane, and optionally drying the resultingcapsules by removing water.

The added components can be added to at least one of oil, water,emulsifier, and at least one of a water-soluble monovalent metal salt,polyvalent metal salt, and acid of the emulsion, prior to or afteremulsification. These further components may include one or more of apharmaceutical agent, veterinary agent, a nutritional supplement, anagricultural agent, a food, a cosmetic ingredient, or excipient. Alsoliving material such as cell lines and micro organisms; probiotics andenzymes may be included in the capsules of the invention. Suitablepharmaceutical active agents include without limitation an oil-solubleor insoluble drug, and drugs with a higher water solubility such asParacetamol, and Verapamil HCl. Suitable nutritional supplements includeherbs, roots, leafs, fruits, flowers, grasses, barks, fruit peels, andminerals or trace minerals in ionic or elemental form, such as calcium,magnesium, zinc, selenium and iron. Suitable agricultural active agentsinclude herbicides and insecticides. Other suitable components include,without limitation, dyes; colorants and pigments such as titaniumdioxide and calcium carbonate; plasticizers, such as glycerol, sorbitol,maltitol and polyethylene glycols; stabilizing polymers, such aschitosan; cellulose gums, carrageenan, alginates, propylene glycolalginate, gellan, xanthan gum, locust bean gum, guar, pectins, gumarabic, gum tragacanth, sodium-carboxymethylcellulose, alkyl celluloseethers such as hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose and methylcellulose and agar-agar; preservativessuch as lower alkylparabens, benzoic acid, sodium benzoate, and benzylalcohol; antioxidants such as ascorbic acid, ascorbyl palmitate,sulfites, L-tocopherol, butylated hydroxyanisole and propyl gallate;disintegrating compounds, and other components.

The further components can be added in liquid form, such as simetihiconeor vitamin E (α-tocopherol); in gaseous form such as carbon dioxide andother gases and as solids such as calcium carbonate and insoluble drugs.The solid components can be crystalline or non-crystalline and in theform of powders, fibers, particles, nanoparticles or granules.

Advantages of adding the components to the emulsion include for examplethe ability to add large amounts of active ingredient just prior to thegelation process and to minimize contact with elevated temperatures,water and high shear environment, as this can destroy some components byfor example decomposition, oxidation and re-crystallization. As aresult, the seamless capsules of the present invention can bepharmaceutical, veterinary, agricultural or nutraceutical solid dosageforms and can be used in specialty applications such as paintballs or asa cosmetic product such as bath oils, etc.

Depending on the emulsion used and the components added, the seamlesscapsules can be manipulated to control the release of the activeingredient as desired in its end-use, e.g. in vivo the capsules can bein a form of immediate or delayed release.

The added solid, liquid or gaseous components are mixed, prior to orafter emulsification of the oil, water, an emulsifier, and at least oneof a water-soluble monovalent metal salt, polyvalent metal salt, and anacid, to form a dispersions, and they will appear in amounts of up to85% by weight of the dried capsule. Preferably, the amounts ofcomponents added to the emulsion is present in amounts from 30%-85% byweight of the dried capsule.

Capsules having a polysaccharide gel membrane on the outer surfaces areformed by adding portions of any one of the oil and water emulsions, ordispersions thereof set forth above to an aqueous gelling bath comprisedof at least one ionic polysaccharide, thereby encapsulating the portionsof the emulsion, or dispersion in a polysaccharide gel membrane. Thepolysaccharide gel membrane formed around the portions of the emulsion,or dispersion is the reaction product of ions of the water-solublemonovalent metal salt, polyvalent metal salt or acid that are in theemulsion, with an ionic polysaccharide that is in the gelling bath. Apreferred concentration of ionic polysaccharide in the gelling bath isin the range of 0.1% to 10%, more preferably in the range of 0.5% to 7%by total weight of the gelling bath solution.

Suitable polysaccharides in the context of the present invention includecarrageenans such as kappa, kappaII and iota carrageenans, alginates,chitosans, pectins such as low methoxy and amidated low metoxy pectins,sodium-carboxymethylcellulose, propylene glycol alginate, or mixturesthereof; however, a preferred polysaccharide is an alginate.

Alginates, derived from, inter alia, brown seaweeds (Phaeophyceae sp.)are linear unbranched chemical polymers containing (1-4)-linkedβ-D-mannuronic acid (M) and α-L-guluronic acid (G) residues. Alginatesare not random copolymers, but consist of blocks of similar andalternating residues, for example, MMMM, GGGG, and GMGM, and aregenerally useful in the form of alginic acid or salts thereof.

A suitable alginate in the gelling bath is an alginate having aweight-average molecular weight of 20,000 Daltons to 500,000 Daltons,having a G-content of at least 30%, preferably in the range of 40% to80%, or 50% to 90%. As used throughout, the weight-average molecularweight is calculated by first determining the intrinsic viscosity, thenusing the Mark-Houwink Sakurada Equation, as in Martinsen, et al;“Comparison of Different Methods for Determination of Molecular Weightsand Molecular Weight Distribution of Alginates” (Carbohydr. Polym. 15:171-193). It has been found that a mixture of both low and higherweight-average molecular weight alginates in the gelling bath impartpreferable properties to the alginate gel capsule membrane surroundingthe emulsion. For example, a preferred mixture of alginates is comprisedof (i) an alginate having a low weight-average molecular weight of30,000 Daltons to 40,000 Daltons, and (ii) an alginate having a higherweight-average molecular weight of 150,000 Daltons to 500,000 Daltons.Increasing the ratio of a higher weight-average molecular weightalginate provides a more elastic alginate gel capsule. Increasing theratio of the low weight-average molecular weight alginate provides aless viscous gelling bath and a more favorable rate of capsuleformation. Depending upon the characteristics desired in the alginategel membrane to be formed around the emulsion, a suitable ratio of lowweight-average molecular weight alginate (i) to higher weight-averagemolecular weight alginate (ii) in the gelling bath is in the range of0.1 to 20 of (i) to 1 of (ii) (0.1-20:1), respectively. A preferredratio of low weight-average molecular weight alginate (i) to higherweight-average molecular weight alginate (ii) is in the range of 1 to 16of (i) to 1 of (ii) (1-16:1), respectively. The gelling bath may containadditional components to include, without limitation, dyes, colorants,secondary film formers, plasticizers; such as glycerol, sorbitol,maltitol and polyethylene glycols; emulsion destabilizers, densityadjusters, preservatives, antioxidants, solids, disintegrants,antifoaming agents and other components.

The methods by which the oil and water emulsions, or dispersions areadded to the gelling bath, inter alia, control the size of the capsulesformed. The emulsion, or dispersion which can be in the form of a thickpaste or in the form of a liquid of low viscosity, can be fragmented, orshaped in some manner into portions, either prior to, or simultaneouslywith, its addition to the gelling bath. Suitable methods for adding theemulsion, or dispersion to the gelling bath include, without limitation,dropping the emulsion from a pipette, or a nozzle, extruding theemulsion through a chopping mechanism, molding the emulsion in a castingmold, and other methods.

The seamless capsule of the invention can be made in a variety ofshapes. The shape of the formed capsules can be determined by the methodof adding the emulsion or dispersion to the gelling bath and by thespecific composition of said emulsion or dispersion. When dropping a lowviscosity composition from a pipette the shape of the end capsules willbe spherical, whereas dropping higher viscosity compositions can yieldoval like capsules. Highly viscous compositions can advantageously bemolded or extruded. When using a mold the mold can be selected to givespherical, oval and oblong capsule shapes. When extruding through anozzle and cutting with a cutting device, for example a knife, wire,water jet, laser or an iris shutter-like device, the shape of thecapsules can be determined by the diameter of the hole and length of thecut emulsion fragment. If the diameter of the hole is in the range ofthe length of the fragment, the shape of the capsules can be spherical,and if the length of the fragment exceeds the diameter of the hole theshape of the capsules will be oval, oblong or cylindrical in shape. Dueto the gelation process, the gelled membrane formed on the surface ofthe fragments added to the gelling bath, will undergo a certain amountof contraction, whereas sharp edges will be rounded off. The amount ofcontraction is influenced by the viscosity of the emulsion or the amountof component added to the emulsion vehicle.

The surface of the portions of the emulsion to be added to the gellingbath may be reduced in stickiness prior to adding such to the gellingbath. A reduction in the stickiness of the surface of the portions ofthe emulsion may aid in helping to (a) ensure the complete release ofthe portions from any device used to form, shape (for example, a mold),or transfer the portions to the gelling bath; (b) increase the ease andspeed of handling the portions; and/or (c) avoid agglomeration orsticking of the individual portions of the emulsion as they areinitially added to the gelling bath. The surface of the portions of theemulsion may be reduced in stickiness by any suitable method that doesnot interfere with the formation of the polysaccharide gel membranesurrounding the portions of emulsion once they are added to the gellingbath. Such suitable methods to reduce stickiness of the surface ofportions of the emulsion include, without limitation, i) surface-drying,or ii) surface-hardening each portion of the emulsion, or by iii)applying a surface coating to at least part of each portion of theemulsion. Suitable surface coatings, such as release agents,anti-tacking agents and lubricants include, without limitation,polysaccharides, such as alginates, and other polysaccharides; C₁₀-C₁₅alkyl lactates, such as lauryl lactate; calcium silicate, dioctylmalate, magnesium carbonate, D-mannitol, silica, hydrated silica, talc;oils and hydrated oils, such as castor oil, coconut oil, cottonseed oil,palm oil, soybean oil, jojoba oil, apricot oil, kernel oil, mineral oil,olive oil, sesame oil, walnut oil, wheat germ oil, and other oils;waxes, such as lanolin wax, and other waxes; microcrystalline cellulose;stearates, such as isocetyl stearate, isocetyl stearoyl stearate,isopropyl stearate, magnesium stearate, zinc stearate, and otherstearates; glycerol derivatives, such as glycerol behenate, glycerolcocoate, glycerol dioleate, glycerol dioleate SE, glycerol distearate,glycerol distearate SE, glycerol laurate SE, glycerol oleate SE,glycerol polymethacrylate, glycerol ricinoleate SE, and other glycerolderivatives; fatty acids, such as palmitic acid, lauric acid, stearicacid, and other fatty acids; polyethyleneglycol (PEG) and derivatives,such as PEG-6, PEG-100, PEG-200, PEG-40 stearate, and otherpolyethyleneglycol derivatives; combinations thereof, and other surfacecoatings. More preferably, alginates may be used as the surface coating.In a preferred method, a portion of the emulsion, or dispersion may beshaped, for example, in a mold, wherein at least a part of the mold maybe treated with a suitable surface coating, such as an alginate, priorto molding the portion of emulsion, or dispersion thereby imparting asurface coating to at least part of the portion of emulsion, ordispersion. The mold may be treated with an aliquot of the gelling bathcontaining an alginate into which the portions of emulsion, ordispersion are to be added, or the mold may be treated with differentsolutions of an alginate.

In certain capsule-forming methods, the portions of the emulsion, ordispersion may be added, or deflected in some manner, to the gellingbath at a point below its surface. Preferably, the gelling bath isstirred at a rate sufficient to prevent the capsules from stickingtogether as they are forming.

During the step of encapsulating the oil and water emulsion, ordispersion as set forth above, it is preferable that the gelling bath bemaintained at a temperature of at least 20° C., and, more preferably inthe range of 30° C. to 70° C. Advantageously, the gel membrane formedcan have a higher alginate solids level when performing theencapsulating step at an elevated temperature. In addition, increasingthe temperature may increase the rate of gelation and subsequently lowerprocessing times, and also provides capsules with an improved, shinyappearance. If a secondary film former is preferred in the gelling bathas set forth above, it can be advantageous to add it to the gelling bathat the aforementioned range of elevated temperatures. Solutions ofcertain suitable secondary film formers, such as kappa-, kappaII andiota-carrageenans and agar-agar, form gels at ambient temperature, butare liquids at elevated temperatures. The liquid secondary film former,when fully dissolved in the gelling bath, becomes an integral part ofthe polysaccharide gel capsule, once the capsule forms. Upon cooling,the secondary film-former can solidify, or gel, thereby providing addedstrength to the capsule. Varying concentrations of secondary film-formerprovide varying levels of capsule strength.

Characteristics desired in the capsule can be optimized during the stepof encapsulating by one skilled in the art, depending on the materialsused. In general, this step can be accomplished during a period of timeup to 240 minutes from the start of the addition of portions of the oiland water emulsion, or dispersion preferably during 2 minutes to 60minutes, and more preferably, during 5 minutes to 20 minutes. Capsulesprepared by the methods set forth above have a capsule diameter in therange of 1 millimeter to 40 millimeters, although the diameter of thecapsule prepared is not restricted by the method of preparation. Gelmembrane thickness of capsules prepared by the methods set forth abovegenerally is in the range of 0.3 millimeter to 4 millimeters.

Depending upon the intended end-use of the capsules of the presentinvention, it may be preferable that the capsules be dry. In a dryingstep, the water that is contained in the now-encapsulated oil and wateremulsion and water within the gel membrane itself is removed. Once“dried”, the capsules are considered to be in a “dry form”, although oneskilled in the art will understand that a capsule in dry form caninclude some water, for example, up to about 20%. Preferably the watercontent of the capsules is less than 10% by the total weight of thedried capsules. Once dried, the polysaccharide gel membrane of thecapsule becomes firmer, as it shrinks to form a thinner drypolysaccharide gel film on the outer surface of the capsule. Preferablythe contents within the capsule, after drying is present in the amountof at least 70% by weight of the capsule, more preferably at least 90%by weight. Capsules prepared by the methods of the present invention,comprised of the quantities of contents set forth above advantageouslydo not lose their shape upon drying and therefore appear smooth, andseamless. Also in capsules containing the emulsion, possibly added afurther liquid component, the core changes from non-transparenttransparent as the water in the emulsion, or dispersion is removedduring the drying step. The emulsion can during the drying stepcompletely separate into a clear oily phase, due to destabilization ofthe emulsion, or it can dry by dehydrating and thereby keeping thestructure of the encapsulated emulsion. A smooth and seamless appearanceis preferable when the capsules are to be used, inter alia, as a dosageof a pharmaceutical, a nutritional supplement, a foodstuff, anagricultural product, a fertilizer, or the like. The drying step can beaccomplished by any method which provides capsules in a dry form, suchas, without limitation, drying of capsules exposed to the atmosphere,drying of capsules in a fluidized bed apparatus, drying of capsules in aperforated coating pan, and other methods of drying known in the art.

Additionally, again depending upon the intended end-use of the capsulesof the present invention, it may be advantageous that the capsules becoated with, for example, a secondary film-former, or a sequestrant, ora secondary film-former and a sequestrant. Coating of capsules of thepresent invention is preferred, for example, when dissolution propertiesof the so-formed capsules need to be altered, when water and mammalianbody solubility need to be altered, to increase capsule strength, tochange the color of the capsules, to alter the gas permeability of thecapsules, and for other purposes known by one skilled in the art.Secondary film-formers include, without limitation, gelling ornon-gelling polymers, and enteric polymers for example, alginates,propylene glycol alginate, carrageenans, pectins such as high methoxy(HM), low methoxy (LM), and amidated low methoxy pectins, chitosans,sodium carboxymethylcellulose, carboxymethylcellulose, cellulose acetatephthalate, cellulose acetate succinate, methyl cellulose phthalate,ethylhydroxycellulose phthalate, polyvinylacetatephtalate,polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer,styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acidcopolymer, methacrylate-methacrylic acid-octyl acrylate copolymer andother enteric polymers, cetyl hydroxyethyl cellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellullose, methylcellulose and other cellulose derivatives,lanolin wax, polyvinyl acetate, polyvinyl pyrrolidone, polyvinylalcohol, guar gum, acacia gum, gellan gum, locust bean gum, xanthan gum,gum tragacanth, starches, maltodextrins, and other secondaryfilm-formers.

The capsule dissolution profiles can be modified to be immediate releaseor enteric or delayed release, dependent on the type of polysaccharideand other materials such as secondary film formers that are used, aswell as the amounts of such. The definitions of “enteric”, “immediaterelease” and “delayed release”, are those established by the USPharmacopoeia, and such definitions are hereby incorporated byreference. The polysaccharides, secondary film formers and othermaterials that can be used to modify such properties are also disclosedin the US Pharmacopeia and examples of such are incorporated herein byreference. Examples of secondary film formers of enteric type includecellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate,polyvinylacetatephtalate, polyvinylbutyrate acetate, vinylacetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer,methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylicacid-octyl acrylate copolymer, or mixtures thereof. Secondary filmformers of immediate release include compounds such as propylene glycolalginate, polyvinyl alcohol, carrageenans, pectins, chitosans, guar gum,gum acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, starches,maltodextrins or mixtures thereof. The secondary film formers can beadded to the gelling bath in an amount of up to 40% by weight of thesaid gelling bath.

Sequestrants include, without limitation, sodium citrate, phosphatesalts, ethylenediaminetetraacetic acid and salts (EDTA), ethyleneglycol-bis(β-aminoethyl ester)-N,N,N′,N′-tetraacetic acid (EGTA), andother sequestrants. Washing the capsules with an aqueous solution ofalcohol and sequestrants can also be used to increase the watersolubility of the capsules.

The capsules of the invention might be washed or rinsed with an aqueoussolution such as water, or an aqueous alcohol solution after theencapsulation step, and prior to the optional drying and coating step.The washed or rinsed capsules of the invention might also possibly betransferred to a hardening bath, before they are dried and coated.

Although the drying and coating of the capsules can be done separatelyand in no special order, a preferred method in the context of thepresent invention is to conduct the drying step and coating stepsimultaneously. The simultaneous drying and coating of the capsules canbe accomplished, for example, by 1) subjecting the wet capsules topre-drying for a short period of time (about 10 minutes) in a fluidizedbed apparatus, 2) adding a solution of a coating, then 3) subjecting thecoated capsules to another, usually longer drying period, affording thecapsules in dry form. A “fluidized bed apparatus” is a device that canbe used for drying and/or coating capsules, in which the capsules areplaced in a stream of air (the fluid) at a velocity to cause thecapsules to float in the stream of air, thereby causing them to dry. Onesuch device is sold under the name and trademark of STREA-1,manufactured by Niro-Aeromatic Ltd, Hauptstrasse 145, CH-4416 Bubendorf,Switzerland.

The capsules of the present invention in dry form may have varyingcapsule diameters depending on the intended use; e.g., the capsulediameter can be relatively small or somewhat larger, and be in the rangeof 0.5 millimeter to 35 millimeters, where the dry polysaccharide gelfilm generally has a thickness in the range of 40 μm to 500 μm.

It is expected that polysaccharide capsules within the scope of thepresent invention, prepared by methods set forth herein, could beprepared either in a continuous process, or a batch-wise process,whichever method is preferable for the production of suitable capsules.

The term “plasticizer” means any compound or material which, when addedto the emulsion or gelling bath, aids in binding water to thepolysaccharide capsule membrane once it is formed, thereby promotingsoftening of the capsule membrane. Plasticizers may also be added to theemulsion in order to softening the contents of the capsules. The term“secondary film formers” means any compound or material which, whenadded to the gelling bath, or coated onto the capsule in a separatestep, aids in altering capsule properties, for example, strength,elasticity, gas permeability, solubility, and appearance. The term“stabilizing polymers” means any compound or material which, when addedto the emulsion, aids in stabilizing the oil and water emulsion byincreasing the viscosity of the water-phase. The term “emulsiondestabilizers” means any compound or material which, when added to thegelling bath, promotes destabilization of the emulsion in the gellingbath. The term “density adjuster” means any compound or material which,when added to the gelling bath, promotes submergence of the emulsion inthe gelling bath. The term “sequestrant” means any compound or materialwhich, when used as a capsule treatment, binds or complexes the calcium,or other gelling ions, in the polysaccharide capsule membrane or film,thereby changing the physical characteristics of the capsule, forexample, making the capsules more water-soluble. The term “antioxidant”means any compound or material which, when added to the emulsion orgelling bath, aids in preventing oxidation of active ingredient, forexample, an oil. The term “preservative” means any compound or materialwhich, when added to the emulsion or gelling bath, aids in preventingbacterial growth within the capsule. The term “ambient temperature”means a temperature in the range of 20° C. to 30° C.

The term “antifoaming agent” means a compound, which prevents foamingwhen added to the gelling bath.

The term “dispersion” means a system in which particles of any nature,e.g. solid, liquid or gas, are dispersed in a continuous phase of adifferent composition or state.

The present invention is now described in more detail by reference tothe following examples, but it should be understood that the inventionis not construed as being limited thereto. Unless otherwise indicatedherein, all parts, percents, ratios, and the like are by weight.

Example 1 Preparation and Alginate Encapsulation of a Water-in-OilEmulsion Soy Oil

A solution of 15.0 grams of calcium chloride dehydrate (Merck, Germany)in 10.0 grams of water was added to a mixture of 0.0001 gram ofpolyglycerol polyricinoleate (Emulsifier-PGPR 90) and 75.0 grams of soyoil (Mills, Norway). The mixture was vigorously stirred for about 30seconds using a homogenizer, affording a water-in-oil emulsion. Theemulsion was then dropped portion-wise into a gelling bath comprised of2.0 grams of higher weight-average molecular weight alginate (PROTANALSF 200, MW=387,000 Daltons; FMC Corporation, Philadelphia, Pa.), 16.0grams of low weight-average molecular weight alginate (PROTANAL LFR5/60, MW=35,000 Daltons; FMC Corporation), 20.0 grams of glycerol(plasticizer), 2.0 grams of polyoxyethylene(20) sorbitan monolaurate(emulsion destabilizer, Tween 20, Fluka), 500 grams of ethanol (96%Arcus, Norway) (emulsion destabilizer-density adjuster), and 1460 gramsof water. The gelling bath was stirred at a moderate rate, while beingmaintained at a temperature of 22° C. The addition of emulsion wascomplete in about 9 minutes, after which time the so-formed capsulesremained in the gelling bath during a period of about one hour. Afterthis time, the capsules were strained from the gelling bath, and rinsedwith water, providing alginate capsules having a diameter of about 4 mm.The capsules were then dried during about 18 hours on a laboratory benchwith air circulating over them from a fan. Upon completion of drying, aportion of the capsules were placed in a sequestrant bath of 100 gramsof a solution aqueous of 0.1 Molar trisodium citrate dihydrate (Merck),2% glycerol, and 20% ethanol for about 90 minutes. After this time thecapsules were removed from the sequestrant bath, rinsed with water, anddried as set forth above. A sample of the capsules was placed in water,where the capsules dissolved in about 15 minutes. Capsules not treatedwith the sequestrant did not dissolve in water.

Example 2 Preparation and Carrageenan Encapsulation of a Water-in-OilEmulsion Soy Oil

An water-in-oil emulsion was prepared in a manner analogous to that ofExample 1, wherein the water-in-oil emulsion was comprised of 65.0 gramsof soy oil, 1.0 gram of calcium chloride dihydrate, 6.5 grams ofpotassium chloride (Merck), and 10.0 grams of deionized water, affordingthe water-in-oil emulsion. The water-in-oil emulsion was added to agelling bath, also prepared in a manner analogous to that of Example 1,wherein the gelling bath is comprised of 4.5 grams of kappa carrageenan(FMC Corp.), 75.0 grams of ethanol (emulsion destabilizer-densityadjuster), 0.3 gram of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20), and 220.2 grams of deionized water. Uponcompletion of addition, the so-formed carrageenan capsules were kept inthe gelling bath during about a one-hour period before recovering anddrying in a manner analogous to that of Example 1 affording roundcapsules of about 4 mm in diameter.

Example 3 Preparation and Carrageenan-Alginate Encapsulation of aWater-in-Oil Emulsion Soy Oil

A water-in-oil emulsion was prepared in a manner analogous to that ofExample 1, wherein the water-in-oil emulsion was comprised of 65.0 gramsof soy oil, 16.1 grams of calcium chloride dihydrate, and 6.4 grams ofdeionized water, affording the water-in-oil emulsion. The water-in-oilemulsion was added to a gelling bath, also prepared in a manneranalogous to that of Example 1, wherein the gelling bath was comprisedof 0.75 gram of carrageenan, 0.75 gram of higher weight-averagemolecular weight alginate (PROTANAL SF 200), 0.30 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20), 3.0grams of glycerol, and 295.2 grams of deionized water. Upon completionof addition, the so-formed carrageenan-alginate capsules were kept inthe gelling bath during about a one-hour period before recovering anddrying in a manner analogous to that of Example 1, affording roundcapsules of about 8-9 mm in diameter.

Example 4 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Soy Oil

With moderate-speed stirring using a homogenizer, 130.0 grams of soy oilwas slowly added to a solution of 7.0 grams of calcium chloridedihydrate, 0.8 gram of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20) and 10.0 grams of deionized water. Upon completionof addition, the mixture was vigorously stirred for about 2 minutesusing a homogenizer, affording an oil-in-water emulsion. The emulsionwas then added by dropping portions of the emulsion through a nozzle (7mm in diameter) into a gelling bath comprised of 12.0 grams of higherweight-average molecular weight alginate (PROTANAL LF 10/60; MW=180,000Daltons; FMC Corporation), 48.0 grams of low weight-average molecularweight alginate (PROTANAL LFR 5/60), 240.0 grams of glycerol(plasticizer) and 2100 grams of deionized water. The gelling bath wasstirred at a moderate rate, while being maintained at a temperature ofabout 60° C. The addition of the emulsion was complete in about 2minutes. Upon completion of addition, the so-formed alginate capsuleswere kept in the gelling bath during about a 30-minute period. Duringthe 30-minute period, aliquots of the capsules were removed at 5, 10,15, and 30 minutes of time in the gelling bath. A portion of eachaliquot of capsules was dried in a manner analogous to that ofExample 1. The dried capsules were then analyzed for elasticity andbreaking strength by subjecting samples of the capsules to compressiontests using a texture analyzer (TA-XT2, manufactured by Stable MicroSystems, Vienna Court, Lammas Road, Godalming, Surrey GU7 1Y1, England).Dried and wet capsules were also analyzed for film thickness and gelthickness, respectively, by splitting samples of capsules and viewingthe cross section under a light microscope (OPTIHOT, manufactured byNikon Corporation, Fuji Building 2-3, Marunouchi 3-chrome, Chioda-ku,Tokyo, Japan). As set forth in table 1 below, the results of these testsindicate that as time in the gelling bath lengthens, elasticity of thecapsules decrease; and strength to break, gel thickness before drying,and dry film thickness of the capsules increase.

TABLE 1 Time in Gelling Bath (Minutes) Capsule 5 10 20 30 Elasticity(Force (Kg) to 0.16 0.29 0.39 0.44 Compress 0.5 mm) Strength (Force (Kg)to 11.7 14.8 18.5 18.9 Break) Table 1 continues Gel membrane Thickness0.88 0.98 1.05 1.10 (Before drying) (in mm ) Dry gel Film Thickness 100130 140 150 (in μm)Capsules left in the gelling bath for the entire 30-minute period wereoval in shape, and were about 7 mm in diameter and 11 mm in length. Theelevated processing temperature resulted in faster gelling speed, highersolids content in the gel membrane before drying, and more shinyappearing capsules after drying.

Example 5 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Fish Oil

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 110.9grams of fish oil (Møller's Cod Liver Oil, Peter Møller); 4.0 grams ofcalcium chloride dihydrate, 1.0 gram of polyoxyethylene(20) sorbitanmonolaurate (Emulsifier-Tween 20) and 10.0 grams of deionized water,affording the oil-in-water emulsion. The oil-in-water emulsion was addedto a gelling bath, also prepared in a manner analogous to that ofExample 4, wherein the gelling bath was comprised of 0.6 gram of higherweight-average molecular weight alginate (PROTANAL SF 200), 4.8 grams oflow weight-average molecular weight alginate (PROTANAL LFR 5/60), 15.0grams of glycerol (plasticizer), 60.0 grams of ethanol (emulsiondestabilizer) and 519.6 grams of deionized water. The gelling bath wasmaintained at ambient temperature during the addition of theoil-in-water emulsion. The so-formed alginate capsules were oval inshape, measuring about 8 mm in diameter by about 11 mm in length.Capsules were dried in a manner analogous to that of Example 1.

Example 6 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Mineral Oil

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 111.9grams of mineral oil (White light, Aldrich), 4.0 grams of calciumchloride dihydrate, 1.0 gram of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20) and 10.0 grams of deionized water, affording theoil-in-water emulsion. The oil-in-water emulsion was added to a gellingbath, also prepared in a manner analogous to that of Example 4, whereinthe gelling bath was comprised of 0.6 gram of higher weight-averagemolecular weight alginate (PROTANAL SF 200), 4.8 grams of lowweight-average molecular weight alginate (PROTANAL LFR 5/60), 15.0 gramsof glycerol (plasticizer), 60.0 grams of ethanol (emulsion destabilizer)and 519.6 grams of deionized water. The gelling bath was maintained atambient temperature during the addition of the oil-in-water emulsion.The so-formed alginate capsules were oval in shape, measuring about 8 mmin diameter by about 11 mm in length. Capsules were dried in a manneranalogous to that of Example 1.

Example 7 Preparation and Chitosan Encapsulation of an Oil-in-WaterEmulsion Soy Oil

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 70.0 gramsof soy oil, 2.2 grams of sodium polyphosphate (Calgon) (polyvalent metalsalt), 0.8 gram of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20) and 10.0 grams of deionized water, affording theoil-in-water emulsion. The gelling bath was prepared by dissolving 15.0grams of glycerol (plasticizer) and 6.0 grams of chitosan (C1210,Pronova Biopolymer) in 279.0 grams of deionized water. A 150.0-gramaliquot of the chitosan solution was then diluted with 150.0 grams ofdeionized water. The oil-in-water emulsion prepared above was addeddrop-wise to the chitosan solution. The gelling bath was maintained atambient temperature during the addition of the oil-in-water emulsion.Upon completion of addition, the so-formed chitosan capsules were keptin the gelling bath during a 30-minute period before recovering anddrying in a manner analogous to that of Example 1, affording roundcapsules of about 7 mm in diameter.

Example 8 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Soy Oil: Coating with an Alginate Secondary Film

An oil-in-water emulsion was prepared in a mariner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 115.7grams of soy oil, 3.0 grams of calcium chloride dihydrate, 0.8 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 10.0grams of deionized water, affording the oil-in-water emulsion. Theoil-in-water emulsion was added to a gelling bath, also prepared in amanner analogous to that of Example 4, wherein the gelling bath wascomprised of 0.6 gram of higher weight-average molecular weight alginate(PROTANAL SF 200), 4.8 grams of low weight-average molecular weightalginate (PROTANAL LFR 5/60), 15.0 grams of glycerol (plasticizer), 60.0grams of ethanol (emulsion destabilizer) and 519.6 grams of deionizedwater. The gelling bath was maintained at ambient temperature during theaddition of the oil-in-water emulsion. Upon completion of addition, theso-formed alginate capsules were kept in the gelling bath during a90-minute period before recovering, affording oval capsules of about 7-8mm in diameter and 10 mm length. The recovered capsules were then placedin a fluidized bed apparatus at ambient temperature where they weredried during about a 10-minute period. A coating solution was prepared,comprised of 7.5 grams of alginate (PROTANAL LF 10/60), 7.5 grams ofglycerol (plasticizer), and 235.0 grams of water. After the 10-minutedrying period, 100 grams of the coating solution was added portion-wiseto the capsules, during about a 45-minute period. After a period ofabout 80 minutes from commencing the drying and coating procedure, thecapsules were removed from the fluidized bed apparatus and placed on alaboratory bench top open to the atmosphere, where they continued to dryduring about 18 hours. After this time, the capsules were, analyzed forelasticity, breaking strength, and film thickness in a manner analogousto that of Example 4. An aliquot of uncoated capsules was also dried forcomparison tests. As set forth in table 2 below, the results of thesetests indicate that the coated capsules were about as elastic asuncoated capsules, but were about four times more resistant to breakage.The film thickness was doubled in the coated capsule.

TABLE 2 Capsule Uncoated Coated Elasticity (Force (Kg) to 0.46 0.54Compress 0.5 mm) Strength (Force (Kg) to 4.3 17.8 Break) Dry Gel filmThickness 80 160 (in μm)

Example 9 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Soy Oil: Coating with an Alginate Secondary Film and a SodiumCitrate Sequestrant

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 109.8grams of soy oil, 3.0 grams of calcium chloride dihydrate, 0.8 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 10.0grams of deionized water, affording the oil-in-water emulsion. A gellingbath was prepared, also in a manner analogous to that of Example 4,wherein the gelling bath was comprised of 1.8 grams of higherweight-average molecular weight alginate (PROTANAL SF 200), 14.4 gramsof low weight-average molecular weight alginate (PROTANAL LFR 5/60),45.0 grams of glycerol (plasticizer), and 1738.8 grams of deionizedwater. About 600.0 grams of the gelling bath was separated, and theoil-in-water emulsion prepared above was added to it, as set forth inExample 4. The gelling bath was maintained at ambient temperature duringthe addition of the oil-in-water emulsion. Upon completion of addition,the so-formed alginate capsules were kept in the gelling bath during a120-minute period before recovering, affording oval capsules of about 10mm length and 7-8 mm in width. The recovered capsules were then placedin a fluidized bed apparatus at ambient temperature where they weredried during about a 13-minute period. A coating solution was prepared,comprised of 3.0 grams of alginate (PROTANAL LF 10/60), 5.2 grams oftrisodium citrate dihydrate (sequestrant), and 91.8 grams of water.After the 13-minute drying period, 67 grams of the coating solution wasadded portion-wise to the capsules, during about a 40-minute period.After this time, the capsules were removed from the fluidized bedapparatus and placed on a laboratory bench top open to the atmosphere,where they were dried during about 18 hours. When placed in water, thecapsules coated in the foregoing manner showed increased solubilityafter about 30 minutes. For comparison tests, an aliquot of coated anduncoated capsules were dried and analyzed in a manner analogous to thatof Example 4. As set forth in table 3 below, the results of these testsindicate that the uncoated capsules were more elastic and more resistantto breakage than the coated capsules. The film thickness was more thandoubled in the coated capsule.

TABLE 3 Capsule Uncoated Coated Elasticity (Force (Kg) to 0.43 0.76Compress 0.5 mm) Strength (Force (Kg) to 9.2 5.6 Break) Dry Gel filmThickness 90 200 (in μm)

Example 10 Preparation and Alginate Encapsulation of aWater-in-Oil-in-Water Emulsion Soy Oil

A water-in-oil-in-water emulsion was prepared in a two-step procedure.First a water-in-oil emulsion was prepared by adding a solution 0.6 gramof sodium bicarbonate (Prolabo)(water soluble material) in 10 grams ofwater to a mixture of 1.1 grams of polyglycerol polyricinoleate(Emulsifier-PGPR 90) dispersed in 90 grams of soy oil. Upon completionof addition, the mixture was vigorously stirred using a homogenizer,affording a water-in-oil emulsion. Then the water-in-oil emulsion wasslowly added to a solution of 3.0 grams of calcium chloride dihydrate,1.0 gram of polyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween20), and 10 grams of deionized water, affording a water-in-oil-in-wateremulsion. The water-in-oil-in-water emulsion was then added to a gellingbath in a manner analogous to that of Example 1, affording stablealginate gel capsules.

Example 11 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Soy Oil: Shaping the Emulsion in Mold Treated with a SurfaceCoating

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 173.5grams of soy oil, 4.5 grams of calcium chloride dihydrate, 1.2 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 15.0grams of deionized water, affording the oil-in-water emulsion. A gellingbath was prepared, also in a manner analogous to that of Example 4,wherein the gelling bath was comprised of 0.6 gram of higherweight-average molecular weight alginate (PROTANAL SF 200), 4.8 grams oflow weight-average molecular weight alginate (PROTANAL LFR 5/60), 15.0grams of glycerol (plasticizer), and 600 grams of deionized water. Aflexible, plastic mold was treated by either spraying or smearing a thinfilm of an aliquot of the gelling bath-alginate solution, as preparedabove, into the 1 cm high by 1.5 cm wide wells of the mold. Portions ofthe emulsion, as prepared above, were then placed into the wells of themold, thereby imparting a surface coating to at least part of theportions of emulsion. The portions of the emulsion were allowed to standin the mold during a period of about 5 to 20 seconds, and then they wereadded to the gelling bath by inverting the mold over the gelling bathand gently squeezing the shaped portions of emulsion out of the mold.The portions of emulsion exited the mold easily, without alteration oftheir shape. Once in the gelling bath, alginate capsule formationproceeded in a manner analogous to that of Example 4. Capsules wereremoved from the gelling bath and dried, also in a manner analogous tothat of Example 4. The process was repeated by spraying or smearing themold with an aqueous 1% solution of higher weight-average molecularweight alginate (PROTANAL SF 200). The process was yet again repeated byspraying or smearing the mold with an aqueous 1% solution of lowweight-average molecular weight alginate (PROTANAL LFR 5/60). In bothrepeat processes, the portions of emulsion exited the mold easily,without alteration of their shape.

Example 12 Preparation and Alginate-Pectin Encapsulation of anOil-in-Water Emulsion Soy Oil

With moderate-speed stirring using a homogenizer, 400 grams of soy oilwas slowly added to a solution of 20.0 grams of calcium chloridedihydrate, 4.0 grams of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20) and 40.0 grams of deionized water. Upon completionof addition, the mixture was vigorously stirred for about 2 minutesusing a homogenizer, affording an oil-in-water emulsion. The emulsionwas then added as cylindrical fragments, obtained by extruding theemulsion through a hole (7 mm diameter) and manually cutting with ametal knife, into a gelling bath comprised of 12.0 grams of lowweight-average molecular weight alginate (PROTANAL LFR 5/60), 18.0 gramsof pectin (Grindsted AMD 780, Danisco Ingredients, USA), 60.0 grams ofglycerol (AnalR, BDH, VWR International, Ltd., UK) and 510 grams ofdeionized water. The gelling bath was stirred at a moderate rate, whilebeing maintained at a temperature of about 22° C. The addition of theemulsion was complete in about 2 minutes. Upon completion of addition,the so-formed alginate-pectin capsules were kept in the gelling bath foranother 19 minutes. The capsules were strained from the bath and rinsedwith water to remove non-reacted gelling bath. The capsules were driedin a manner analogous to Example 1, yielding oval shaped capsules with adiameter of 7 mm and a length of 14 mm. The dried capsules had a totalwater content of about 3.8 wt %.

Example 13 Preparation and Alginate-Propylene Glycol Alginate (PGA)Encapsulation of an Oil-in-Water Emulsion Soy Oil: Acid DisintegratingCapsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 390 gramsof soybean oil, 12.0 grams of calcium chloride dihydrate, 3.0 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 30.0grams of deionized water, affording the oil-in-water emulsion. Theoil-in-water emulsion was added to a gelling bath in a manner analogousto example example 12 wherein the gelling bath was comprised of 6.0grams of low molecular weight alginate (PROTANAL LFR 5/40 RB), 24.0grams of low molecular weight proplylene glycol alginate (PGA) (DuckloidSLF-3, Kibun) 60.0 grams of glycerol (AnalR)(plasticizer), and 510.0grams of deionized water. The emulsion was added to the gelling bathduring 2 minutes, and kept in the bath for another 19 minutes beforethey were collected and rinsed briefly in water. The gelling bath wasmaintained at ambient temperature during the addition and encapsulationof the oil-in-water emulsion. The capsules were dried on a bench withcirculated air from a fan for 48 hours, and after drying, the so-formedalginate-PGA capsules were oval in shape, measuring about 8 mm indiameter by about 13 mm in length and had a water content of 6.4%. Thecapsules comply with the European Pharmacopoeia disintegration test01/2002:0016 for soft capsules using 0.1 M HCl as liquid medium.

Example 14 Preparation and Alginate-Propylene Glycol AlginateEncapsulation of an Oil-in-Water Emulsion Soy Oil: Acid DisintegratingCapsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 390 gramsof soybean oil, 11.0 grams of calcium chloride dihydrate, 1.5 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 30.0grams of deionized water, affording the oil-in-water emulsion. Theoil-in-water emulsion was added to a gelling bath in a manner analogousto example 12 wherein the gelling bath was comprised of 7.2 grams of lowmolecular weight alginate (PROTANAL LFR 5/40 RB), 24.0 grams of lowmolecular weight PGA (Duckloid SLF-3, Kibun) 60.0 grams of glycerol(AnalR)(plasticizer), 80 grams of a 75% maltitol solution (Maltisweet3145, 75%, SPI Polyols, USA) and 428.8.0 grams of deionized water. Theemulsion was added to the gelling bath during 2 minutes, and kept in thebath for another 19 minutes before they were collected and rinsedbriefly in water. The gelling bath was maintained at ambient temperatureduring the addition and encapsulation of the oil-in-water emulsion. Thecapsules were dried on a bench with circulated air from a fan for 48hours, and after drying, the so-formed alginate-PGA capsules were ovalin shape, measuring about 8 mm in diameter by about 14 mm in length. Thecapsules comply with the European Pharmacopoeia disintegration test01/2002:0016 for soft capsules using 0.1 M HCl as liquid medium.

Example 15 Preparation and Alginate-Propylene Glycol AlginateEncapsulation of an Oil-in-Water Emulsion Soy Oil: Additional Hardeningin a Calcium Lactate Solution

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 390 gramsof soybean oil, 11.0 grams of calcium chloride dihydrate, 1.5 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 30.0grams of deionized water, affording the oil-in-water emulsion. Theoil-in-water emulsion was added to a gelling bath in a manner analogousto example 12 wherein the gelling bath comprised of 7.2 grams of lowmolecular weight alginate (PROTANAL LFR 5/40 RB), 24.0 grams of lowmolecular weight PGA (Duckloid SLF-3, Kibun) 60.0 grams of glycerol(plasticizer), and 508.8 grams of deionized water. The gelling bath wasmaintained at ambient temperature during the addition and encapsulationof the oil-in-water emulsion. The emulsion was added to the gelling bathduring 2 minutes, and after another 19 minutes in the gelling bath, thecapsules were collected and rinsed in water for 5 seconds and thentransferred to a hardening bath comprising 1.54 grams of Ca-lactate(Merck), 50 grams of glycerol (plasticizer) and 448.46 grams ofdeionized water. Capsules were left in the hardening bath for about 5minutes. The capsules were dried on a bench with circulated air from afan for 48 hours. After drying, the so-formed alginate-PGA capsules wereoval in shape, measuring about 8 mm in diameter by about 14 mm in lengthand had a water content of 7.4%. The capsules comply with the EuropeanPharmacopoeia disintegration test 01/2002:0016 for soft capsules using0.1 M HCl as liquid medium.

Example 16 Preparation and Alginate-Carrageenan-Propylene GlycolAlginate (PGA) Encapsulation of an Oil-in-Water Emulsion Soy Oil: AcidDisintegrating Capsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 480 gramsof soybean oil, 20.0 grams of calcium chloride dihydrate, 4.0 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 40.0grains of deionized water, affording the oil-in-water emulsion. Agelling bath comprised of 15.0 grams of low molecular weight alginate(PROTANAL LFR 5/60), 15.0 grams of kappa carrageenan (A-CAT, FMCCorporation), 60.0 grams of low molecular weight PGA (Duckloid SLF-3,Kibun) 150.0 grams of glycerol (plasticizer), and 1260.0 grams ofdeionized water was made by dissolving the alginate, carrageenan and PGAin the deionized water at 80° C. under vigorously stirring for 20minutes. To 500 grams of the above-mentioned gelling bath, the emulsionwas added in a manner analogous to example 12 during 2 minutes, and keptin the bath for another 19 minutes before they were collected and rinsedbriefly in water. The gelling bath was maintained at 35° C. during theaddition and encapsulation of the oil-in-water emulsion. The capsuleswere dried on a bench with circulated air from a fan for 48 hours, andafter drying, the so-formed alginate-carrageenan-PGA capsules were ovalin shape, measuring about 8 mm in diameter by about 13 mm in length. Thecapsules comply with the European Pharmacopoeia disintegration test01/2002:0016 for soft capsules using 0.1 M HCl as liquid medium.

Example 17 Preparation and Alginate-Polyvinyl Alcohol (PVA)Encapsulation of an Oil-in-Water Emulsion Soy Oil: Acid DisintegratingCapsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 269.8grams of soybean oil, 10.0 grams of calcium chloride dihydrate, 2.0grams of polyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20)and 20.0 grams of deionized water, affording the oil-in-water emulsion.24.1 grams of the oil-in-water emulsion was added to a gelling bath in amanner analogous to Example 12 wherein the gelling bath was comprised of6.0 grams of low molecular weight alginate (PROTANAL LFR 5/60), 18.0grams of Polyvinyl alcohol (PVA) (MW 30.000-70.000 Daltons, Sigma), 60.0grams of glycerol (AnalR)(plasticizer), 120 grams of a 75% maltitolsolution (Maltisweet 3145, 75%, SPI Polyols, USA) and 396.0 grams ofdeionized water. The emulsion was added to the gelling bath during 2minutes, and kept in the bath for another 19 minutes before they werecollected and rinsed briefly in water. The gelling bath was maintainedat ambient temperature during the addition and encapsulation of theoil-in-water emulsion. The capsules were dried on a bench withcirculated air from a fan for 48 hours, and after drying, the so-formedalginate-PVA capsules were oval in shape, measuring about 8 mm indiameter by about 13 mm in length. The capsules comply with the EuropeanPharmacopoeia disintegration test 01/2002:0016 for soft capsules using0.1 M HCl as liquid medium.

Example 18 Preparation and Alginate-Cellulose Acetate PhthalateEncapsulation of an Oil-in-Water Emulsion Enhancing Enteric Properties

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 600 gramsof soybean oil, 25.0 grams of calcium chloride dihydrate, 4.0 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 50.0grams of deionized water, affording the oil-in-water emulsion. Theabove-mentioned oil-in-water emulsion was then added to a gelling bathin a manner analogous to example 12, wherein the gelling bath wascomprised of 9.0 grams of higher weight-average molecular weightalginate (PROTANAL LF 10/60), 6.0 grams of low weight-average molecularweight alginate (PROTANAL LFR 5/60), 60.0 grams of glycerol(plasticizer), 12.0 grams of cellulose acetate phthalate (EastmanChemical Company, USA) and 513.0 grams of deionized water, where thegelling bath was adjusted with 1 M NaOH-solution to pH 11. The additionto the gelling bath lasted for 2 minutes, and the forming capsules werekept in the bath for another 19 minutes before they were collected andrinsed briefly in water. The gelling bath was maintained at ambienttemperature during the capsule formation. The capsules were dried in amanner analogous to that of Example 1, and after drying, the so-formedalginate capsules were oblong in shape, measuring about 7.5 mm indiameter by about 13 mm in length. The so-formed capsules comply withthe European Pharmacopoeia test 01/2002:0013 for gastro-resistantcapsules, using 50 mM phosphate buffer pH 6.8.

Example 19 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion High Solid Content-Calcium Carbonate

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 80 gramsof soybean oil, 4.0 grams of calcium chloride dihydrate, 1.0 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 10.0grams of deionized water, affording the oil-in-water emulsion. A mixtureof 35 grams of calcium carbonate (Merck) and 20 grams of theabove-mentioned oil-in-water emulsion was then added to a gelling bathin a manner analogous to example 12, wherein the gelling bath wascomprised of 9.0 grams of higher weight-average molecular weightalginate (PROTANAL LF 10/60), 6.0 grams of low weight-average molecularweight alginate (PROTANAL LFR 5/60), 60.0 grams of glycerol(plasticizer), and 525.0 grams of deionized water. The addition to thegelling bath lasted for 2 minutes, and the forming capsules were kept inthe bath for another 19 minutes before they were collected and rinsedbriefly in water. The gelling bath was maintained at ambient temperatureduring the capsule formation. The capsules were dried in a manneranalogous to that of Example 1, and after drying, the so-formed alginatecapsules were oblong in shape, measuring about 7.5 mm in diameter byabout 12 mm in length and had a water content of 1.0%. The amount ofcalcium carbonate in the final dried capsules was calculated to 62%.

Example 20 Preparation and Alginate Encapsulation of an Oil-in-WaterEmulsion Soy Oil: Stability of Dried Capsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 1000 gramsof soy oil, 50.0 grams of calcium chloride dihydrate, 10.0 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 100.0grams of deionized water affording the oil-in-water emulsion. 132 gramsof the prepared emulsion was then added in a manner analogous theExample 12 into a gelling bath comprised of 50.0 grams of higherweight-average molecular weight alginate (PROTANAL LF 10/60), 200.0grams of low weight-average molecular weight alginate (PROTANAL LFR5/60), 1000 grams of Sorbitol Special (SPI Polyols, USA) and 8750 gramsof deionized water. The gelling bath was stirred at a moderate rate,while being maintained at a temperature of about 60° C. The addition ofthe emulsion was complete in about 2 minutes. Upon completion ofaddition, the so-formed alginate capsules were kept in the gelling bathfor another 19 minutes. The capsules were strained form the bath andrinsed with water to remove non-reacted gelling bath. The capsules weredried in a manner analogous to Example 1. After drying the capsules wereput into both closed and open plastic containers and inserted into anincubator at 40° C. and 75% relative humidity. During a period of 6months the capsules were evaluated, and results are given in table 4below. The capsules were of oval-type shape. Disintegration test wasperformed according to Ph. Eur. 4, 01/2002:0016, test for gastroresistant capsules, using 50 mM phosphate buffer pH 6.8.

TABLE 4 Weeks 0 4 4 12 12 26 26 Container Start Open Closed Open ClosedOpen Closed Testing parameters Strength, Force 1224 382 661 362 429 576565 0.5 mm compression (g) STDEV (g), n = 5 66 221 198 45 48 102 33Strength, Force 16.7 12.2 16.4 13.4 12.9 13.7 15.2 break (kg) STDEV(kg), n = 5 3.7 3.8 1.8 2.9 3.8 2.4 3.1 Dry Gel film 150 110 110 110 110130-140 130-140 thickness (in μm) Oil leakage None None None None NoneNone None Capsule breakage None None None 2/14 None 2/14 NoneDisintegration Complies Not Not Complies Complies Complies Complies withtest tested tested with test with test with test with test STDEV =standard deviation of measurements of 5 capsules.

Example 21 Preparation and Alginate-Carrageenan Encapsulation of anOil-in-Water Emulsion Soy Oil: Stability of Dried Capsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 109.5grams of soy oil (Mills, Norway), 4.0 grams of calcium chloridedihydrate (Merck), 1.0 g Potassium chloride (Merck), 1.0 gram ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 12.0grams of deionized water, affording the emulsion. A part of the preparedemulsion was then added in a manner analogous to the one in Example 12into a gelling bath comprised of 12.0 grams of low weight-averagemolecular weight alginate (PROTANAL LFR 5/60), 12.0 grams of kappacarrageenan (A-CAT, FMC Corporation) 60.0 grams of Sorbitol Special (SPIPolyols, USA) and 516 grams of deionized water. The gelling bath wasstirred at a moderate rate, while being maintained at a temperature ofabout 60° C. The addition of the emulsion was complete in about 2minutes. Upon completion of addition, the so-formed alginate-carrageenancapsules were kept in the gelling bath for another 19 minutes. Thecapsules were strained from the bath and quickly rinsed with water toremove non-reacted gelling bath. The capsules were dried in a manneranalogous to Example 1. After drying the capsules were put into closedplastic containers and inserted into an incubator at 40° C. and 75%relative humidity. During a period of 6 months the capsules wereevaluated, and results are given in table 5 below. The capsules were ofoval-type shape. Disintegration test was performed according to Ph. Eur.4, 01/2002:0016, test for soft capsules using 0.1 M HCl as liquidmedium.

TABLE 5 Weeks 0 4 12 26 Testing parameters Strength, Force 0.5 mm 331124 99 85 compression (g) STDEV (g), n = 5 16 10 19 5 Strength, Forcebreak (kg) 9.1 8.6 8.6 4 STDEV (kg), n = 5 2.2 1.1 0.9 1.3 Dry Gel filmthickness 170 210 230 220 (in μm) Oil leakage None None None NoneCapsule breakage None None None None Disintegration Complies Not testedComplies Complies with test With test with test STDEV = standarddeviation of measurements of 5 capsules.

Example 22 Preparation of an Oil-in-Water Emulsion Soy Oil: Stability ofEmulsion as Function of Time and Temperature

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 520 gramsof soy oil, 14.0 grams of calcium chloride dihydrate, 4.0 grams ofpolyoxyethylene(20) sorbitan monolaurate (Emulsifier-Tween 20) and 40.0grams of deionized water, affording an oil-in-water emulsion. 5measuring cylinders (25 ml) were filled to the top with about 30 gramsof the emulsion, covered with parafilm and kept for 24 hours at 5° C.,20° C., 40° C., 60° C. and 80° C. and visually examined. No signs ofdestabilization were observed during this period for all temperatures.The emulsion in the cylinder kept at 80° C. was after 24 hourstransferred to 20° C. and visually examined for another 35 days. Nosigns of destabilization were observed during this period.

Example 23 Film Thickness, Variability, and Film Weight Versus CapsuleWeight Comparison with Commercially Available Gelatin Capsules

An oil-in-water emulsion was prepared in a manner analogous to that ofExample 4, wherein the oil-in-water emulsion was comprised of 131.5grams of soy oil (Mills, Norway), 6.0 g of calcium chloride dihydrate(Merck), 1.0 grams of polyoxyethylene(20) sorbitan monolaurate(Emulsifier-Tween 20, Fluka) and 10.0 grams of deionized water,affording an oil-in-water emulsion. 19.8 grams of the prepared emulsionwas then added in a manner analogous the Example 12, using a diameter ofthe hole of 6 mm, into a gelling bath comprised of 12.0 grams of higherweight-average molecular weight alginate (PROTANAL LF 10/60), 18.0 gramsof low weight-average molecular weight alginate (PROTANAL LFR 5/60),180.0 grams of glycerol (AnalR) and 990 grams of deionized water. Thegelling bath was stirred at a moderate rate, while being maintained at atemperature of about 25° C. The addition of the emulsion was complete inabout 2 minutes. Upon completion of addition, the so-formed alginatecapsules were kept in the gelling bath for another 19 minutes. Thecapsules were strained from the bath and rinsed with water to removenon-reacted gelling bath. The capsules were dried in a manner analogousto Example 1, yielding oblong shaped capsules with a diameter of 6.8 mmand a length of 9.8 mm. The dried capsules had a total weight of about250 milligrams, and a wall weight of about 41 milligrams. The totalamount of water in the dried capsule was calculated to 6.2% by weight.Film thickness of the above described capsules and the capsules ofExample 12 and Example 17 was compared with 4 commercially availablegelatin capsules. The film thickness was obtained by measuring the filmthickness of the cross-sectional cut of the capsules. Capsules werephotographed using a Kappa CF 11/1 camera (Kappa messtechnik gmbh,Gleichen, Germany) on top of a Nikon SMZ-10 stereoscopic microscope(Nikon Corporation), printouts of the photographs were manuallyevaluated and film thickness was calculated at 8 equally spacedpositions. The exception was capsules from Example 17, were the thinfilm made this methods difficult to perform and the capsule weremeasured directly at 8 equally spaced positions in a Nikon OPTIHOTmicroscope. The results are given in table 6 below. The average (AVE)and the relative standard deviation (% RSD) of the film thickness werecalculated. The calculations of the film weight vs. the total weight (wt% Film) were for all capsules performed by dividing the film weight withthe total capsule weight. The film weight was obtained after removingthe contents of the capsules and thoroughly wiping the capsule shellclean.

TABLE 6 AVE % wt % Capsule Manufacturer/batch (μm) RSD Film Example 12FMC 161 2.5 16 Example 17 FMC 61 5.3 5.7 Example 22 FMC 157 7.2 16Gelatine Triomega ®, 452 16.2 32 Pronova Biocare, 215741A Gelatine,Mintec ™, Monmouth Pharmaceuticals 526 13.9 39 enteric Ltd, UKBN95822EC/1 Gelatine Möller's Dobbel, 514 12.3 36 Peter Möller, NorwayL93468 Gelatine Triomega Kids ®, Pronova Biocare, 559 11.7 35 4210104/1TD3057

Those of ordinary skill in the art will appreciate that variations ofthe invention may be used and that it is intended that the invention maybe practiced otherwise than as specifically described herein.Accordingly, the invention includes all modifications encompassed withinthe spirit and scope of the invention as defined by the followingclaims.

1. A seamless capsule comprising a polysaccharide gel membrane on theouter surface and optionally a coating on said gel membrane, wherein:(i) said capsule encapsulates an emulsion comprising at least one oil,water and at least one emulsifier and said emulsion is an oil-in-wateremulsion, (ii) said oil is present in an amount of at least 50% byweight of said emulsion, (iii) said polysaccharide gel membrane is anionic gel membrane comprising at least one of alginate, propylene glycolalginate or pectin and said at least one of alginate, propylene glycolalginate or pectin is a salt of calcium, strontium, barium or aluminum,(iv) said capsule is oblong, oval, or cylindrical, (v) said capsule isenteric or delayed release, and (vi) said emulsion does not containmarmelo mucilage.
 2. The seamless capsule of claim 1, wherein thecapsule is dried.
 3. The seamless capsule of claim 1, having a wetcapsule diameter in the range of 1 millimeter to 40 millimeters, whereinsaid gel membrane has a thickness in the range of 0.3 millimeters to 4millimeters.
 4. The seamless capsule of claim 1, wherein said capsule isdried and said gel membrane is a dry polysaccharide gel film on theouter surface which constitutes up to 30% by weight of the driedseamless capsule.
 5. The seamless capsule of claim 4, wherein the drypolysaccharide gel film constitutes up to 10% by weight of the driedcapsule.
 6. The seamless capsule of claim 1, having a dry capsulediameter in the range of 0.5 millimeter to 35 millimeters, wherein saiddry polysaccharide gel film has a thickness in the range of 40 μm to 500μm.
 7. The seamless capsule of claim 1, wherein said polysaccharide gelmembrane is an alginate gel membrane.
 8. The seamless capsule of claim1, wherein said gel membrane further comprises one or more secondaryfilm formers selected from cellulose acetate phthalate, celluloseacetate succinate, methyl cellulose phthalate, ethylhydroxycellulosephthalate, polyvinylacetatephtalate, polyvinylbutyrate acetate, vinylacetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer,methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylicacid-octyl acrylate copolymer, or mixtures thereof.
 9. The seamlesscapsule of claim 1, wherein said emulsion is dehydrated and keeps thestructure of said emulsion.
 10. The seamless capsule of claim 1, whereinsaid emulsion further comprises at least one component chosen from apharmaceutical agent, a veterinary agent, a nutritional supplement, anagricultural agent, a cosmetic ingredient, a colorant, and a food. 11.The seamless capsule of claim 10, wherein the at least one component isa pharmaceutical agent.
 12. The seamless capsule of claim 1, whereinsaid oil is present in said oil-in-water emulsion in an amount of from70% by weight to 98% by weight of said oil, water, and at least oneemulsifier.
 13. The seamless capsule of claim 12, wherein said oil ispresent in said oil-in-water emulsion in an amount of from 85% by weightto 95% by weight of said oil, water, and at least one emulsifier. 14.The seamless capsule of claim 1, wherein said at least one ionicpolysaccharide is an alginate having a weight-average molecular weightof from 20,000 Daltons to 500,000 Daltons.
 15. The seamless capsule ofclaim 14, wherein said at least one ionic polysaccharide comprises amixture of: (i) an alginate having a weight-average molecular weight offrom 30,000 Daltons to 40,000 Daltons, and (ii) an alginate having aweight-average molecular weight of from 150,000 Daltons to 500,000Daltons.
 16. The seamless capsule of claim 15, wherein said mixture of(i) and (ii) is in a ratio of from 0.1 to 20:1.
 17. The seamless capsuleof claim 16, wherein said ratio is from 1 to 16:1.
 18. The seamlesscapsule of claim 14, wherein said ionic gel membrane comprises analginate having a G content of at least 30%.
 19. The seamless capsule ofclaim 14, wherein said polysaccharide gel membrane comprises an alginatehaving a G content of from 40% to 80%.
 20. The seamless capsule of claim14 wherein said polysaccharide gel membrane comprises an alginate havinga G content of from 50% to 90%.
 21. The seamless capsule of claim 10,wherein the at least one component is a nutritional supplement.
 22. Theseamless capsule of claim 1, wherein said oil is a pharmaceutical agent,a nutritional supplement, a flavor oil, or a food.
 23. The seamlesscapsule of claim 22, wherein said oil is a pharmaceutical agent.
 24. Theseamless capsule of claim 1, wherein said oil is a carrier for at leastone oil soluble active material and said at least one oil soluble activematerial comprises a pharmaceutical agent, a nutritional, flavor,fragrance, or a food.
 25. The seamless capsule of claim 1, wherein saidoil comprises at least one of fatty acids or esters.
 26. The seamlesscapsule of claim 1, wherein said oil is fish oil.
 27. The seamlesscapsule of claim 22, wherein said oil is a nutritional supplement. 28.The seamless capsule of claim 1, with the proviso that said emulsiondoes not contain a strengthening polymer.
 29. The seamless capsule ofclaim 1, wherein said emulsion consists of said oil, water, emulsifierand optionally at least one of a pharmaceutical agent, veterinary agent,nutritional supplement, agricultural agent, food, cosmetic ingredient,excipient, cell lines, microorganisms, probiotics, enzymes, dyes,colorants, pigments, plasticizers, preservatives, and antioxidants.